This project currently is directed toward the elucidation of mechanism(s) of drug transport, intracellular binding, distribution and detoxification. Current studies of a novel oxathiin carboxanilide (NSC 615985) identified by the primary NCI anti-HIV screen have established that its cellular transport (1) is characterized by a rapid association with the target HIV cells; (2) is markedly temperature sensitive and (3) is linear over the in vitro therapeutic range. An additional objective of this project is to increase drug efficacy by modulation of drug transport and detoxification. Increased cellular accumulation of oxathiin carboxanilide has been achieved by using a series of classical multiple drug resistance (MDR) chemosensitizers. Conversion of the active compounds to inactive intermediates in vitro by esterase has been recently demonstrated; future work will be directed toward characterization of substrate specificity of these compounds for esterase, and the investigation, in vitro and in vivo, of specific inhibitory regimens designed to block detoxification.